The ability of cells and organisms to regulate protein homeostasis, or the balance of protein synthesis, assembly, folding, aggregation and secretion in the endoplasmic reticulum (ER) is critical to normal cell function and viability. Deficiencies i the ER proteostatic network are implicated in aging and many types of human disease including metabolic and neurodegenerative disorders, cancer and cardiac maladies. In order to protect protein homeostasis in the ER and throughout the secretory pathway, cells have evolved three mechanistically distinct signaling arms that regulate ER proteostasis, collectively referred to as the unfolded protein response (UPR). While the three arms of the UPR were originally considered to be a global response to ER stress, recent evidence suggests that selective modulation of specific arms of the UPR could play a role in normal development and be manipulated to treat protein misfolding diseases. Our objective is to unravel the chemistry and biology of arm-selective UPR activation by examining the relative contributions of specific arms of the UPR in response to particular stressors, such as the type and magnitude of the protein misfolding burden, and how that selectivity changes as a function of cell and tissue type (Specific Aim 1). Moreover, we are developing reporters for arm-specific UPR activation, which are being applied to discover small molecule arm-specific activators or inhibitors of the UPR (Specific Aim 2). The discovery of arm-selective UPR modulators could lead to the development of therapeutic agents for the treatment of protein misfolding diseases. PUBLIC HEALTH RELEVANCE: The ability to selectively activate or inhibit specific arms of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) is desirable in order to develop therapies for the treatment of numerous protein misfolding disorders, such as neurodegenerative disease, metabolic disorders and cancer. We are developing sensitive reporters for arm-selective activation of the UPR to learn how each specific arm of the UPR in various cells and tissues contributes to protection from disease- associated protein misfolding stressors and to discover small molecule arm-specific UPR modulators. Elucidating the specific activation profiles relevant to particular disease states and discovering molecules which can selectively modulate particular arms of the UPR could lead to the development of small molecule therapeutics for the treatment of protein misfolding diseases, for example lysosomal storage disease or -1 anti-trypsin associated emphysema.